The invention relates to novel compounds and pharmaceutically acceptable salts thereof, their use, either alone or in combination with other therapeutic agents, in the treatment or prophylaxis of HIV infection, and to pharmaceutical compositions comprising these compounds.
The disease known as acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the strain known as HIV-1. In order for HIV to be replicated by a host cell, the information of the viral genome must be integrated into the host cell""s DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. The HIV replication cycle therefore requires a step of transcription of the viral genome (RNA) into DNA, which is the reverse of the normal chain of events. An enzyme that has been aptly dubbed reverse transcriptase (RT) accomplishes the transcription of the viral RNA into DNA. The HIV virion includes a copy of RT along with the viral RNA.
Reverse transcriptase has three known enzymatic functions; it acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell""s genome by another enzyme called integrase.
Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), d4T, 3TC, Nevirapine, Delavirdine, Efavirenz and Abacavir, the main drugs thus far approved for use in the treatment of AIDS.
As with any antiviral therapy, use of RT inhibitors in the treatment of AIDS eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterized, and resistance to known therapeutic agents is due to mutations in the RT gene. Some of the most commonly observed mutants clinically are: the Y181C mutant, in which a tyrosine (Y), at codon 181, has been mutated to a cysteine (C) residue, and K103N where the lysine (K) at position 103 has been replaced by asparagine (N). Other mutants, which emerge with increasing frequency during treatment with known antivirals, include the single mutants V106A, G190A, Y188C, and P236L; and the double mutants K103N/Y181C, K103N/P225H, K103N/V108I, and K103N/L100I.
As therapy and prevention of HIV infection using antivirals continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, with different patterns of effectiveness against the various mutants.
Compounds having tricyclic structures, which are inhibitors of HIV-1, are described in U.S. Pat. No. 5,366,972. Other inhibitors of HIV-1 reverse transcriptase are described in Hargrave et al., J. Med Chem., 34, 2231 (1991).
U.S. Pat. No. 5,705,499 proposes 8-arylalkyl- and 8-arylheteroalkyl-5,11-dihydro-6H-dipyrido[3,2-B:2xe2x80x2,3xe2x80x2-E][1,4]diazepines as inhibitors of RT.
WO 01/96338 and U.S. Pat. No. 6,420,359 disclose diazepine structures having quinoline and quinoline-N-oxide substituents as inhibitors of RT. The exemplified compounds have activity against HIV WT, single and double mutant strains. WO 02/076982 and WO 03/011862 also disclose diazepine structures having substituents structurally different from the present invention.
The present invention provides novel compounds that are potent inhibitors of wild type and double mutant strains of HIV-1 RT. Advantageously, the compounds of the present invention are effective at inhibiting the clinically significant double mutant K103N/Y181C.
In a first aspect of the invention, there is provided a compound represented by formula I: 
wherein
R2 is selected from the group consisting of H, (C1-4)alkyl, halo, haloalkyl, OH, (C1-6)alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2;
R4 is H or Me;
R5 is H or Me;
R11 is H, (C1-4)alkyl, (C3-4)cycloalkyl and (C1-4)alkyl-(C3-4)cycloalkyl;
A is a connecting chain of (C1-3)alkyl;
B is O or S;
n is 0 or 1;
wherein when n is 0:
Ring C is 6- or 10-membered aryl or 5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from the group consisting of O, N, and S,
said aryl and said heterocycle being optionally substituted with from 1 to 4 substituents selected from the group consisting of:
halogen and (C1-6)alkyl optionally substituted with OH;
and E is selected from:
(i) CONR12R13 wherein R12 and R13 is each independently H, SO2(C1-6)alkyl, (C1-6)alkyl-COOH, (C1-6)alkyl-(C3-7)cycloalkyl said cycloalkyl being optionally substituted with COOH;
(ii) CONHNR14R15 wherein R14 and R15 is each independently H or (C1-6)alkyl optionally substituted with COOH;
(iii) NR16COR17 wherein R16 is H or (C1-6)alkyl optionally substituted with COOH or (C6-10)aryl-COOH; and
R17 is (C2-4)alkenyl-COOH, (C3-7)cycloalkyl-COOH, NH(C1-6)alkyl-COOH; (C1-6)alkyl optionally substituted with COOH; or (C1-6)alkyl-(C3-7)cycloalkyl said cycloalkyl being optionally substituted with COOH;
(iv) NR18SO2(C1-6)alkyl wherein R18 is H or (C1-6)alkyl;
(v) SO2NR19R20 wherein R19 is H or (C1-6)alkyl; and R20 is (C1-6)alkyl optionally substituted with COOH; and
(vi) SO2R21 wherein R21 is (C1-6)alkyl;
or
when n is 1:
Ring C is as defined above; and
E is a single bond or a connecting group selected from: 
wherein R22 is H or (C1-6)alkyl; 
wherein R23 is H or (C1-6)alkyl; 
wherein R24 is H or (C1-6)alkyl; 
wherein R25 is H or (C1-6)alkyl; 
wherein R26 and R27 is each H or (C1-6)alkyl; 
wherein R28 is H or (C1-6)alkyl; 
wherein R29 is H or (C1-6)alkyl; and 
and
Ring D is a 6- or 10-membered aryl or a 5- or 6-membered heterocycle having from 1 to 4 heteroatoms selected from the group consisting of O, N, and S, said aryl and said heterocycle being optionally substituted with from 1 to 5 substituents selected from:
halogen, NH2, NO2, COOH, OH, COO(C1-6) alkyl, (C1-6)alkoxy, (C2-4)alkenyl-COOH, (C3-7)cycloalkyl-COOH and (C1-6)alkyl optionally substituted with COOH or OH;
or a salt or a prodrug thereof.
According to a second aspect of the invention, there is provided a pharmaceutical composition for the treatment or prevention of HIV infection, comprising a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
According to a third aspect of the invention, there is provided a method for the treatment or prevention of HIV infection, comprising administering to a patient an HIV inhibiting amount of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
According to a fourth aspect of the invention, there is provided a method for treating or preventing HIV infection comprising administering a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, in combination with an antiretroviral drug.
According to a fifth aspect of the invention, there is provided a method for preventing perinatal transmission of HIV-1 from mother to baby, comprising administering a compound of formula I, as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to the mother before giving birth.
According to a sixth aspect of the invention, there is provided the use of a compound of formula I, as described herein, for the manufacture of a medicament for the treatment or prevention of HIV infection.